Constitutively active GPR43 is crucial for proper leukocyte differentiation
Constitutively active GPR43 is crucial for proper leukocyte differentiation
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DOI：
10.1096/fj.202201591r
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发表时间：
2022-12
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通讯作者：
Sosuke Miyasato;Kurumi Iwata;Reika Mura;S. Nakamura;K. Yanagida;H. Shindou;Y. Nagata;M. Kawahara;S. Yamaguchi;J. Aoki;A. Inoue;Teruyuki Nagamune;Takao Shimizu;Motonao Nakamura
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作者：
Sosuke Miyasato;Kurumi Iwata;Reika Mura;S. Nakamura;K. Yanagida;H. Shindou;Y. Nagata;M. Kawahara;S. Yamaguchi;J. Aoki;A. Inoue;Teruyuki Nagamune;Takao Shimizu;Motonao Nakamura
G蛋白偶联受体GPR43(游离脂肪酸受体2，FFA2)和GPR41(游离脂肪酸受体3，FFA3)被不同条件下产生的短链脂肪酸激活，包括碳水化合物的微生物发酵。以前的研究已经表明，这种受体的能量平衡和免疫反应，以及细胞生长停滞和细胞凋亡。在这里，我们观察到这两种受体在人类血细胞中的表达，并在白血病细胞系(HL-60、U937和THP-1细胞)分化过程中显著增强。报告实验表明，GPR43与GαI和Gα12/13偶联，并且在没有任何刺激的情况下具有结构性活性。GPR43、GLPG0974和CATPB的特异性阻断剂作为反向激动剂发挥作用，因为这些化合物的治疗显著降低了结构性活性。在HL-60细胞中，GPR43的表达增强通过Gα12/13导致生长停滞。此外，GPR43的活性被阻断后，由于黏附分子的减少，这些细胞的黏附性能显著降低。我们进一步揭示了增强的GPR43活性诱导了F-肌动蛋白的形成。然而，由于反向激动剂对细胞死亡无效，GPR43的活性在丁酸诱导分化的HL-60细胞凋亡中没有作用。总而言之，这些结果表明，具有结构性活性的GPR43对生长停滞至关重要，随后是白细胞的适当分化。
The G protein‐coupled receptors, GPR43 (free fatty acid receptor 2, FFA2) and GPR41 (free fatty acid receptor 3, FFA3), are activated by short‐chain fatty acids produced under various conditions, including microbial fermentation of carbohydrates. Previous studies have implicated this receptor energy homeostasis and immune responses as well as in cell growth arrest and apoptosis. Here, we observed the expression of both receptors in human blood cells and a remarkable enhancement in leukemia cell lines (HL‐60, U937, and THP‐1 cells) during differentiation. A reporter assay revealed that GPR43 is coupled with Gαi and Gα12/13 and is constitutively active without any stimuli. Specific blockers of GPR43, GLPG0974 and CATPB function as inverse agonists because treatment with these compounds significantly reduces constitutive activity. In HL‐60 cells, enhanced expression of GPR43 led to growth arrest through Gα12/13. In addition, the blockage of GPR43 activity in these cells significantly impaired their adherent properties due to the reduction of adhesion molecules. We further revealed that enhanced GPR43 activity induces F‐actin formation. However, the activity of GPR43 did not contribute to butyrate‐induced apoptosis in differentiated HL‐60 cells because of the ineffectiveness of the inverse agonist on cell death. Collectively, these results suggest that GPR43, which possesses constitutive activity, is crucial for growth arrest, followed by the proper differentiation of leukocytes.